In 2018, the U.S. finds itself trapped in the sinking hole of an opioid crisis.
The National Institute on Drug Abuse reported that an average of 115 people die from opioid overdoses every day. Between 21 and 29 percent of patients who are given prescription opioids misuse them, which can often lead these patients to heroin. And, closer to home, the Midwest saw a 70 percent rise in opioid overdoses from July 2016 to September 2017.
IU researchers are involved in the fight to end opioid addiction, focusing on elements like prioritizing harm reduction, removing legal barriers and improving treatment services.
They have also even conducted studies on treatments and alternatives to opioids. In Feb. 2018, lead investigator Andrea G. Hohmann and other researchers in the Linda and Jack Gill Center for Biomolecular Science at IU presented research about a failed osteoarthritis drug that has the potential to block neuropathic pain and decrease signs of opioid dependence.
More researchers should also consider researching clinical, safer alternatives to opioids.
The danger of prescription opioids such as fentanyl lies in the side effects. Although they reduce pain, prescription opioids generate a particularly intense dopamine reward cycle in the brain, requiring increasing dosages to continue providing pain relief. When patients misuse their prescriptions, they can become addicted and risk overdosing. And if they try to stop, the withdrawal symptoms can quite literally kill when left untreated. People can actually die from opiate withdrawal.
It therefore makes sense to search for an alternative solution to pain that leaves risky side effects at the door. In particular, some researchers are asking if, rather than mask pain with a screen of drugs, you could somehow turn pain off directly.
One way of doing this might be through a little nerve receptor called NaV1.7, which is involved in the firing of pain nerve cells.
Why does this receptor attract our attention? Consider a handful of individuals who were discovered to have congenital insensitivity to pain, meaning that they can break their limbs without much batting an eye. It turns out they all showed mutations in a gene called SCN9A, which is responsible for coding the NaV1.7 receptor. The mutations rendered the receptor inactive, and this is why these subjects couldn’t feel pain.
On the other hand, people with primary erithermalgia are extremely sensitive to pain, experiencing a burning sensation of the feet and lower limbs when exposed to even small amounts of warmth. These patients exhibit a mutation that is also in SCN9A, but one that makes the NaV1.7 receptor excessively active, causing the pain cells to fire too easily.
What these extreme cases indicate is that the NaV1.7 receptor is necessary for pain. In fact, it seems to be the pain nerve cell’s loudest voice, most involved in whether or not the cell will send signals. If we can control this receptor, then we can control pain. So, how do you stop it?
One highlight to note about NaV1.7 is that it is found primarily in the peripheral nervous system, the nerves outside the brain and spinal column. This means that molecules targeting it can be kept out of the central nervous system through the blood-brain barrier, thus avoiding the side effects we see with opioids.
Considering that this receptor contains a pore into the nerve cell, one solution may be to plug it up. However, this has proved challenging. The shape of the pore is extremely similar to those of other NaV receptors, so it’s hard to make something that blocks the NaV1.7’s pore specifically. After all, you don’t want to accidentally block the heart’s NaV1.5, or the muscles’ NaV1.4, or this could lead to heart failure or paralysis.
Consequently, some scientists are trying to target not the pore itself, but the domains around the pore that help it function. These domains are unique to each kind of NaV receptor, so they can be targeted more selectively. For example, experiments at Xenon Pharmaceuticals and Genentech showed that aryl sulfonamides can deactivate one domain of NaV1.7, which prevents the channel from opening in mice. More work needs to be done, however, because these molecules still latch on to important NaV receptors in other parts of the body, such as the heart and brain.
Toxins from spider venom, on the other hand, seem more promising. Similar to the molecules previously mentioned, spider venom contains large proteins that can disable NaV1.7 by way of the domains as well.
For example, synthetic molecules, based on tarantula venom toxins, reduced pain in mice almost entirely. At the same time, the molecules were significantly more selective of NaV1.7 over other kinds of NaV channels, which means they would do their jobs precisely and effectively.
Although 10 years have passed since research began on suppressing NaV1.7, scientists still have many questions. No drug is yet clinical, and there is still a lot of mystery surrounding how the inhibitors we have found work. Nevertheless, the research has been progressing steadily forward, and if a solution can be found, we might have an effective, nonaddictive alternative to the opioids that are ravaging the country today.
